Diabetic retinopathy is the leading cause of blindness among adults in the U. S. Retinal neurons are particularly vulnerable in the disease and die shortly after its onset. This death of retinal neurons is at least partly due to changes in retinal energy status, as metabolic utilization of glucose, the principal metabolic substrate in retina, is severely compromised in diabetes. Interestingly, the mechanism by which cells in the retina are energized during diabetes, these neurons must rely upon other monocarboxylates, namely ketone bodies, to meet their high energy demands because of impairment of glucose utilization. Until recently, uptake of monocarboxylates by retinal cells was thought to be mediated soley by the proton-coupled monocarboxylate transporters (MCTs). Recently, two new transporters with novel energetic features have been identified which mediate the cellular uptake of lactate and ketone bodies in a sodium-coupled electrogenic manner. We have evidence to show that these two transporters, known as SMCT1 and SMCT2, are expressed in the retina with a very interesting and intriguing expression pattern with the different cell types. SMCT1 is expressed exclusively in retinal neurons and RPE whereas SMCT2 principally in Muller cells. We hypothesize that these two transporters are important determinants of energy status in retinal neurons and thus are directly relevant to retinal function in diabetes when ketone bodies replace glucose as the energy source. The goal of the current project is to understand the physiologic, pathologic, and clinical relevance of SMCT1 and SMCT2 in the retina, particularly the relevance of these transporters in retinal ganglion cells, Muller cells, and RPE. We will also investigate the importance of circulating lactate and ketone bodies to retinal energy status under normal and diabetic conditions using a novel mouse model which shows markedly reduced levels of these metabolites in blood due to impaired renal reabsorption. These studies are critical to understand the molecular events associated with diabetic retinopathy as SMCT1 and SMCT2 are likely to be very important to the maintenance of energy status of retinal neurons and thus may play a role in supporting survival of the retinal neurons in diabetes. [unreadable] [unreadable] [unreadable] [unreadable]